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Harrison began playing tee ball at three years old. Before playing in organized baseball, Harrison displayed interest in the game. Using a fork from his home's kitchen as a bat and a balled-up piece of paper, Harrison played makeshift baseball with his older brother, Vince, who pitched the paper to him.[1]

Harrison played shortstop at Princeton High School in Cincinnati, Ohio.

Harrison had his contract purchased by the Pirates on May 30, 2011.[4] Harrison made his major league debut on May 31, 2011, and recorded his first Major League hit, off New York Mets pitcher R.A. Dickey. On May 18, 2012, he broke up Justin Verlander's no-hitter in the ninth inning, which would have been the third no-hitter of Verlander's career.

Harrison was optioned to the Triple-A Indianapolis Indians on April 14, 2013.[5] He was recalled on May 7 when James McDonald was placed on the disabled list. Harrison was optioned back to Indianapolis on May 8 when Duke Welker was recalled.[6] Harrison was optioned back to Indianapolis on May 31.[7]

On July 6, 2014, Harrison was selected to his first career All-Star Game, along with fellow teammates Andrew McCutchen and Tony Watson.[8] At the time of his selection, Harrison was hitting .298 through 72 games. Harrison also had played 5 different positions throughout the season, and was listed as a utility player for the All-Star Game.

Since then he's played multiple positions for the Pirates. But most recently he's played mostly Third Base following Pedro Álverez's move to 1st Base. Harrison finished 2014 with the best statistics of his career with a .315 batting average (second in the NL), 13 home runs, 52 runs batted in, and finished ninth in voting for NL MVP.[9]

Harrison is the nephew of former Major League outfielder and current Milwaukee Brewers coach John Shelby. Harrison's brother, Vince Harrison, played minor league baseball from 2001-2011, before joining the Pirates organization as a player-coach.[1][10]